19-bisdifluoro pregnanes



anti-estrogenic hormones.

United States Patent 3,257,435 19-BISDIFLUORO PREGNANES Albert Bowersand James C. Orr, Mexico City, Mexico, assignors to Syntex Corporation,Panama, Panama, a

corporation of Panama No Drawing. Filed Sept. 21, 1962, Ser. No. 225,396

Claims. (Cl. 260-39145) In the above formulas Z represents a double bondor a saturated linkage between C1 and 0-2; X represents hydrogen,fluorine or chlorine, all having a or [3 configurations; Y represents afi-hydroxyl or a keto group; W represents hydrogen, fluorine orchlorine; R represents a hyd roxyl group; T represents hydrogen,oc-hYdIOXY, a-. acyloxy, a-methyl or B-methyl; T and R togetherrepresent the group in the 16a,17a-positions, wherein R and R eachrepresents hydrogen or a hydrocarbon residue of up .to 8 carbon atoms ofstraight, branched, cyclic or mixed aliphaticcyclic chain, or aromatic,such as methyl, ethyl, isopropyl, phenyl, methyl-cyclohexyl and thelike; and R represents hydrogen or a hydrocarbon carboxylic acyl groupof less than 12 carbon atoms.

The acyl groups are derived from hydrocarbon oarboxylic acids containingless than 12 carbon atoms which may be saturated or unsaturated, ofstraight, branched, cyclic or cyclic-aliphatic chain, aromatic and maybe substituted by functional groups such as hydroxy, alkoxy containingup to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro,amino or halogen. Typical ester groups are the acct-ate, p-ropionate,enanthate, benzoate, trimethylacetate, t-butylacetate, p'henoxyacetate,cyclopentylpropionate, aminoacetate, and fi-chloropropionate.

The compounds represented by the above formulas are valuable corticalhormones with high anti-inflammatory, low catabolic, glycogenic andthymolytic activities. In addition, they are anti-androgenic,antigonadotrophic and Furthermore, they have high topical activity inskin disorders such as psoriasis, allergic dermatitis and the like.

The novel compounds of the present invention are prepared by the processillustrated by the following formula scheme:

In the above formulae R, R T, Z, W, and X have the same meaning asdescribed hereinbefore; Z may be a double or single bond between C6 andC7.

In practicing the process outlined above, a 19,19-difluoro-M-pregnen-l7u-ol-3,20-dione derivative (1) is treated withiodine in the presence of calcium oxide to give the corresponding21-iodo derivative, which upon treatment with potassium acetate in asuitable solvent, such as acetone, preferably at reflux temperature,affords the corresponding 21-acetoxy-l9,l9-difluoro-A-pregnenl7a-ol-3,20-dione derivative (II). The latter 3,20-dione uponincubation with adrenal glands in a suitable medium, e.g. an aqueoussolution of alkali metal phosphates and chlorides and magnesium sulfate,mixed with an aqueous solution of fumaric acid andsodium hydroxide, for'a period of time of the order of 3 hours, at approximately 28-37 (3.,yields the corresponding 19,19-difiuoro-M- pregnene-llB,17a,21-triol-3,20dione derivative (III).

The latter 1 118-01 (III) is treated with mesyl chloride indimethylformamide and pyridine, at approximately 80 C., for about halfan hour, to produce the corresponding 19,l-9-difluoro-A-pregnadiene-l7a,21dio1 3,20-dione derivative. The last mounted A-compound is treated with an N-bromoimide or amide, such asN-bromoacetamide, in the presence of perchloric acid, in an inertsolvent, such as for example, dioxane, to give the corresponding A9a-brom-o-11B-ol which upon treatment with a mild base, such aspotassium acetate, in a suitable solvent, e.g. acetone, preferably atreflux temperature, affords the corresponding 19,19-diohloro-9 3,l l,B-oxido-A -pregnene-17a, 2ldiol-3,20-dione compound. The latter95,11,8-oxido compound, upon treatment with a hydrogen halide, such ashydrogen fluoride or hydrogen chloride, in a suitable inert organicsolvent, e.g. methylene chloride or chloroform, yields the corresponding9a-halo-1'9,l9-difluoro- A pregnene-l1B,l7a,2l-triol-3,20-dionederivative (III:

W=halogen).

The llfl-hydroxyl group present in several compounds of this invention(III) after previous conventional protection of the 21- and/or16-hydroxyl groups, as by esterification, is oxidized, preferably withJones reagent (chromium trioxide in sulfuric acid), thus affording thecorresponding ll-ketone (IV).

The compounds of the present invention having a 16cc, 17a-cyclic acetalor ketal grouping, yield the corresponding 16a, 17oc-di0ls byconventional treatment with a strong acid, such as formic acid. Theobtained diols, upon conventional esterification in pyridine with anacylating agent, as for example acetic anhydride or caproic anhydride,afford the corresponding l6-acylates.

The 1604, 17ot-diols upon conventional condensation with a ketone oraldehyde, such as benzaldehyde, acetophenone, methyl ethyl ketone,acetone, and the like, in the presence of an acid, yield thecorresponding 16oz, l7a-methylenedioxy derivatives wherein thesubstituents on the methylenedioxy group may be different from those ofthe previously hydroylzed cyclic acetal or ketal groupmg.

The compound of the present invention having a 21- acyloxy group may besaponified by conventional treatment with the base to produce thecorresponding 2-l-free alcohols which, in turn, may be acylatedconventionally in pyridine with an acylating agent to give thecorresponding ZI-acylates, wherein the acyl .group may be different fromthe previously saponified one.

The following specific examples serve to illustrate the presentinvention, but are not intended to limit the scope thereof:

Example I A cooled solution of 4 g. of 19,19-difiuoro-A -pregnene-17OL-Ol3,20-Cll01'l (obtained according to our copending US. patentapplication Serial No. 225,364, filed September 21, 1962), in 30 cc. oftetrahydrofuran and 18 cc. of methanol was treated under continuousstirring with 6 g. of pure calcium oxide, in small portions, and thenwith 6 g. of iodine. The stirring was continued at room temperatureuntil the solution turned pale yellow. The mixture was poured into icewater containing 18 cc. of acetic acid :and 2 g. of solutionthiosulfate. After stirring for 15 minutes the solution was decanted andthe precipitate was collected by filtration, thus giving the 2l-iododerivative of the starting material.

This compound was mixed with 80 cc. of acetone and 12 g. of recentlyfused potassium acetate and the mixture was refluxed for 8 hours,concentrated to a small volume, diluted with water and extracted withethyl acetate; the extract was washed with water, dried over anhydroussodium sulfate and concentrated until crystallization started. Theprecipitate was collected and crystallized from methanol-water, thusyielding 2l-acetoxy 19,19-difluoro-M-pregnene-l7a-ol-3,20-dione(compound No. 11).

Following exactly the same procedure, the starting compounds listedunder I (obtained in accordance with our aforesaid patent application)were respectively converted into the corresponding products set forthunder II.

4 Example II The following solution A, B and C were prepared usingdistilled water as solvent: solution A-was prepared by mixing 425 cc. ofa 1.742% dipotassic phosphate solution (K HPO with cc. of 1.38%monosodic phosphate; solution B was prepared by diluting a mixture of 11t. of 4.5% sodium chloride solution, 40 cc. of a 5.75% potassiumchloride solution and 10 cc. of a 19.1% magnesium sulfate, to a volumeof 5 1t.; solution C was prepared by dissolving 20.9- g. of fumaric acidand 14.4 g. of sodium hydroxide in 1 lt. of water and diluting thesolution to 1.2 It. Then 475 cc. of solution A, 4.32 lt. of solution Band 1.2 It. of solution C were mixed.

Adrenal glands of recently slaughtered cattle, defatted, were ground ina meat grinder until a homogeneous mass was obtained; to 1 kg. ofhomogenate was added 2 liters of the mixture of A, B, and C solutionswith vigorous stirring. To the mixture there was then added 1 g. of19,l9-difluoro-A -pregnene-17oc,2l-diol 3,20 dione, obtained byconventional saponification of compound No. 1, dissolved in 5.35 partsof propyleneglycol, the mixture was stirred at 28-37 C. for 3 hours, 13liters of acetone were added and the mass was stirred at roomtemperature for an additional 1 hour.

The acetone extract was separated by filtration, the ground adrenalswere washed with 6 liters of acetone, the extracts were combined and thesolvent removed by distillation under reduced pressure. The residue wastreated conventionally with 2 cc. of acetic anhydride in 5 cc. ofpyridine at room temperature overnight. It was then poured into waterand the produced precipitate crystallized, to give 2l-acetoxy-19,19difluoro-A -pregnene-l1B,17a-diol-3,20-dione (compound No. 14)

By the same procedure, the compounds Nos. 2 to 13, inclusive, werefirstly saponifiedand thereafter respectively converted into- CompoundNo.: 15. 2l-acetoxy-19,19-difiuoro-16ot-methyl-A pregnene-l15,17a-di0l-3 ,20-dione. 16. 21-acetoxy-l9,19-difiuoro-16B-methyl-Apregnene-1l/3,17u-diol-3 ,20-dione. 17. 21-acetoxy-19,l9-difluoro-A-pregnadiene- 1 1B, l7a-diol-3,20 dione. 18.21-acetoxy-19,19-difiuoro-16a-methyl-Apregnadiene-l1B,l7a-diol-3,20-dione. l9.2l-acetoxy-19,19-difluoro-l6B-methyl-A pregnadiene-l 1B-17a-diOl3,2OdiOI1e. 20. 2l acetoxy-l9,19-difiuoro-16a-methyl-Apregnadiene-l1,6,17a-diol-3,20-dione. 21.21-acetoxy-6fi-chloro-19,l9-difiuoro-16amethyl-M-pregnene-l1fi,17a-diol-3,20-dione.

Compound No.:

22. 21-acetoxy-6/3,19,19-trifluoro-16a-methyl-A pregnene-3,20dione.

23. 21-acetoxy-6a-chlor0-19,19-difluoro-16umethy1-A -pre gnene-l1B,17a-dio1-3,20dione.

25. 21-acetoxy-6a-chloro-19,19-difluoro-16emethyl-A-pregnadiene-l1fl,17e-diol-3,20-dione.

26. 21-acetoxy-6-chloro-19,19-difiuoro-16ernethyl-A -pregnadiene-11,8,17a-diol-3 ,20-dione.

Example III A solution of 1 g. of 21-acetoxy-19,19-difluoro-Apregnene-l1B,17a-dio1-3,20-dione (Cpd. No 14) in cc. of acetone wascooled to 0 C. and treated under an atmosphere of nitrogen and withstirring, with a solution of 8 N chromic acid (prepared by mixing 26- g.of chromium trioxide with 23 cc. of concentrated sulfuric acid anddiluting with water to 100 cc.), until the color of the reagentpersisted in the mixture. It was stirred for 5 minutes further at 05 C.and diluted with water. The precipitate was collected, washed with waterand dried under vacuum, thus affording a crude product which uponrecrystallization from acetone-hexane gave 21-aceto-xy- 19,19-difluoro-A-pregnene-17a-ol 3,11,20 trione (Cpd. No. 27).

Following the same procedure, there were treated the compounds Nos. to26, inclusive, thus affording re spectively Compound No.2 28.21-acetoxy-19,19 difluoro-16a-methy1-A pregnene-17e-ol-3,11,20-trione.

29. 21-acetoxy-19,19-difluoro-16fi-methy1-A pregnene-17a-ol-3,11,20-trione.

3 0. 21acetoxy-19,19-difluoro-A -pregnadiene- 17 (vol-3,1 1,20-trione. I

31. 21-acetoxy-19,19-difiuoro-16a-methy1-A pregnadiene-17a-0l-3,11,20-trione.

3 2. 2l-acetoxy-19,19-difiuoro-16fi-methyl-A pregnadiene- 17 a-o1-3,11,20-trione.

3 3. 21-acetoxy-19, l9-difluoro-16u-methy1-A pregnadiene-17a-o1-3,11,20trione.

34. 21-a-cetoxy-6B-chloro-19,19-difluoro-16amethyl-A -pregnene- 17owl-3,1 1,20-trione.

35. 21-acetoxy-6fi,19,19-trifiuoro-16u-methyl-A pregnene-17ot-ol-3,11,20-trione.

36. 21-acetoxy-6a-ch1oro-19,19-difiuoro-16amethyl-M-pregnene-17a-0l-3,11 ,ZO-trione.

3 7. 21-acetoxy-6a,19,19-trifluoro-16a-methyl-A pregnene-17u-ol-3,11,20-trione.

3 8. 21-acetoxy-6a-chloro-19,19-difluoro-16amethyl-n -pregnadiene-1705-01-3 ,1 1,20-trione.

39. 2 l-acetoxy-G-chloro-19,19-difluoro-16u-methyl- M -p re gnadiene- 17a-ol-S, 1 1,20-trione.

Example IV 2 g. of 21-acetoxy-19,19-di1iuoro-A -pregnene-115,17-diol-3,20-dione (Cpd. No. 14) was dissolved in 50 cc. of methanol andtreated with 5 cc. of a 4% aqueous solution of potassium hydroxide; thereaction mixture was stirred for 1 hour under an atmosphere of nitrogenat 0 C.; the mixture was neutralized with acetic acid and the methanoldistilled under reduced pressure. The residue was triturated with waterand the solid collected, washed with 'water, dried and recrystallizedfrom ethyl acetate-methanol, thus producing 19,19-difluoro-A-pregnene-l1 3,17u,21-trio1-3,20-dione (Cpd. N0. 40). I

The compounds Nos. 15 to 39, inclusive, were treated following the aboveprocedure thus giving respectively 6 Compound No.2

41. 19,l9-difluoro-16a-methy1-A -pregnene-1113,17u,

2 1-triol-3,20-dione. 42. 19,19-diflu0ro-l 6fi-methyl-A-pregnene-17B,17a,

21-triol-3,20-dione. 43. 19,19-difluoro-A -pregnadiene-11B,17a-21-triol-3,20-dione. 44. 19,19-difluoro-16ot-rnethyl-A -pregnadiene-11,8,17a,21-triol-3,20-dione. 45. 19,19-difluoro-16,8-methyl-A-pregnadiene-115,

17oc,21-1Il0l-3,20-di0116. I 46. 19,19-difluoro-l6a-methyl-A-pregnadiene-11(3 17a,21-triol-3,20-dione. 47.6fl-chloro-19,19-difiuoro-16ot-methyl-Apregnene-l1B,l7or,2l-triol-3,20-dione. 48.6,8,19,19-trifluoro-16u-methyl-A -pregnene- 11B,17a,21-trio1-3,20-dione.49. 6a-chloro-19,l9-difluoro-16a-methyl-A -pregnene-l 1B,17a,21-t1l013,20-d10116. 50. 6a,19,19-trifiuoro-16u-methyl-A-pregnene-',

17a-2 1-triol-3 ,20-dione. 51. 6a-chloro-19,19-difluoro-la-methyl-A-pregnadien-e-l l B,17a,21-trio1-3,20-dione. 52.6-ch1or0-19,19-difluoro-16a-methyl-A pregnadiene-l1B,17a,21-trio1-3,20-dione. 5 3. 19,19-difiuoro-A-pregnene-170:,21-diol-3,11,20-

trione. -54. 19,19-difluoro-16a-methyl-A -pregnene 17a,

21-dio1-3,11,20-dione. 55. 19,19-difluoro-16fi-methyl-A-pregnene-17a,21-

dial-3 ,11,20-trione. 5 6. 19,19-difluoro-A -pregnadiene-17u,21-dio1,3,11,

20-trione. I 57. 19,19-difluoro-16a-methyl-A -pregnadiene-17a,

' 21-dio1-3,11,20-trione. 5 8. 19,19-difluoro-16fl-methyl-A-pregnadiene- 17a,21-dio1-3,11,20-t1'ione. 59.19,l9-difiuoro-16az-methyl-A -pregnadiene-17m 21-diol-3 ,11,20-trione.60. 6fi-ch1oro-19,19-difluoro-16a-methyl-Apregnene-17a,21-diol-3,11,20-trione. 61. 65,19,19-trifluoro-16m-methyl-A-pregnene-17a,

21-diol-3,11,20-trione. 62. 6or-chloro-19,19-difluoro-16a-methy1-Apregnene-17a,21-dio1-3,11,20-trione. 63. 6a,19,19-trifiuoro-16a-methy1-A-pregnene-17a- 21-dio1-3,1 1,20-trione. 64.6a-ch1oro-19,19-difluoro-16a-methyl-A pregnadiene-17a,21-diol-3,11,20trione. 65. 6-chloro-19,19-difiuoro-16a-methy1-A-pregnadiene-17a,21-dio1-3,11,20-trione.

Example V A mixture of 1 g. of 19,19-difluoro-A -pregnene-1lfi,17e,21-triol-3,20-dione (Cpd. No. 40), 4 cc. of pyridine and 2 cc. ofcaproic anhydride was kept at room temperature overnight, poured intoice water, the formed precipitate was filtered, washed with water anddried. Crystallization from acetone-hexane gave 19,19-difluoro- A-pregnene 11B,17a 21 triol 3,20 dione 21 caproate (Cpd. No. 66).

' Thevcompound No. 53 was treated by the sameprocedure, thus affording19,19-difluoro-A -pregnene-170,21- dio1-3,11,20-trione 21-caproate (Cpd.No. 67).

Example VI 19,19 difluoro ;,l7oc isopropylidenedioxy Apregnene-3,20-dione (obtained in accordance With our aforesaid US.patent application) was treated successively according to Examples 1,II, and III, thus yielding respectively: 21-acetoxy-19,19-difluoro16a,17a-isopropylidenedioxy-A -pregnene-3,20-dione (Cpd. No. 68), 21-acetoxy 19,19 difluoro 1611,1700 isopropylidenedioxy- A-pregnene-1lfl-ol-3,20-dione (Cpd. No. 69) and 21- acetoxy 19,19difluoro 1611,17 isopropylidenedioxy- A -pregnene-3,11,20-trione (Cpd.No. 70).

7 Example VII The compounds Nos. .69 and 70, were treated in accordancewith Example IV thus alfording respectively: 19,19 difluoro 16a,17 xisopropylidenedioxy A pregnene-l1[3,21-diol-3,20-dione (Cpd. No. 71) and19,19- difluoro 16oc,l7ot isopropylidenedioxy A pregnene-21-o1-3,l1,20-trione (Cpd. No. 72).

Example VIII 1 g. of 19,19-difiuoro-l6a,17a-isopropylidenedioxy-Apregnene-l1fi,21-diol-3,20-dione (Cpd. No. 71) .was heated on the steambath with 20 cc. of 60% formic acid for 1 hour, cooled, diluted withwater and the precipitate was collected, washed with water, dried, andrecrystallized from acetone-hexane, thus affording 19,19- difluoro Apregnene 11/5,16a,l7a,21 tetrol 3,20- dione (Cpd. No. 73).

Following the same procedure compound No. 72 was converted into19,19-difluoro-A -pregnene-16a,17a,21- triol-3,11,20-trione (Cpd. No.74).

Example IX The compounds Nos. 73 and 74 were treated in accordance withExample V thus aflording respectively: 19,19- difluoro A pregnenellfi,l6oc,l7oc,2l tetrol 3,20- dione 16,21-dicaproate (Cpd. N0. 75) and19,19-difiuoro- A pregnene 16oc,170c,2l .triol 3,11,20-trione 16,21dicaproate (Cpd. No. 76).

Example X 19,19 diflllOIO-I6oc,l7oc isopropylidenedioxy Apregnatriene-3,20-dione (obtained in accordance with our aforementionedapplication) was treated following successively the procedures describedin Examples I, II and 1H, thus yielding respectively:2l-acetoxy-19,19-difiuoro- 16a,17a-isopropylidenedioxy Apregnatriene-3,20- dione (Cpd. No. 77),2l-acetoxy-l9,l9-difluoro-16a,17aisopropylidenedioxy A pregnatrieneIla-016,20- dione (Cpd. No. 78) and 21-acetoxy-19,l9-difluoro-16a,17a-isopropylidenedioxy A -pregnatriene-ll1,20-trione (Cpd. No. 79).

Example XI The compounds Nos; 78 and 79 were treated in accordance withExample IV, thus yielding respectively: 19,l9-difluoro-16a,17uisopropylidenedioxy A -pregnatriene-l1B,21-diol-3,20-dione (Cpd. No. 80)and 19,19 difiuoro-l6tx,l7a isopropylidenedioxy A -pregnatriene-21-ol-3,11,20-trione (Cpd. No. 81).

Example XII The compounds Nos. 80 and 81 were treated in accordance withExample VIII, thus yielding respectively: 19,19-difiuoro-Apregnatriene-ll,8,16a,17a,21-tetrol- 3,20-dione (Cpd. No. 82) and19,19-di-fluoro-A -pregna-triene-16a,17a,21atriol-3,11,20-trione (Cpd.No. 83).

Example XIII 10 g. of 21-acetoxy 19,19 difluoro-A -pregnene-llfi,17a-diol-3,20-dione (Cpd. No. 14) was dissolved with slow heating in 125cc. of dimethyl-formamide, the mixture was cooled, 4.2 g. of mesylchloride and cc. of pyridine were added and the solution was kept at 80C. for half an hour. The reaction mixture was cooled, water was addedand the product was extracted with ethyl acetate. The extract was washedwith water, dried over anhydrous sodium sulfate and the solvent wasevaporated. Recrystallization of the residue from acetone-hexanefurnished 21-acetoxy-19,19-difiuoro-A pregnadien- 17a-ol-3,20-dione(Cpd. No. 84).

2.8 g. of N-bromoacetamide were added to a mixture of 5 g. of compoundNo. 84, 50 cc. of pure dioxane and 0.8 cc. of 0.4 N perchloric acidwhile stirring in the dark and at room temperature during 1 hour. Thereaction mixture was stirred for 1 hour further, a solution of 7 sodiumsulfate was then added until the potassium-starch g indicator paper-n0longer turned blue, ice was added, the mixture was extracted withchloroform and the extract was washed consecutively with water, 5%aqueous sodium bicarbonate solution and water, and the solvent wasremoved by distillation under vacuo. By trituration of the residue withacetone there was obtained the corresponding 9aHbromo-11B-hydroxyderivative.

A mixture of 2 g. of anhydrous potassium acetate and 20 cc. of acetonewas heated almost to boiling and then a solution of 1.7 g. of the abovebromohydrin in 20 cc. of acetone was added slowly while stirring; themixture was then refluxed for 10 hours, cooled and almost all of theacetone was distilled off; iced-water was then added, the precipitatewas filtered, washed with water and dried. Upon recrystallization frommethylene chloride-benzene there was obtained 21 acetoxy 19,19difluoro-9B,1l 3- oxido-A -pregnen-17a-ol-3,20-dione (Cpd. No. 85).

In a polyethylene flask, adapted with magnetic stirrer, there wasdissolved 1 g. of Compound No. 85 in 30 cc. of methylene chloride, thesolution was cooled to 0 C. and a solution of 2.11 g. of anhydroushydrogen fluoride in 3.7 cc. of tetrahydrofurane cooled in a Dry Iceacetone bath C.) was added over a period of 20 minutes with constantstirring. The mixture was stirred at a temperature lower than 10 C. for6 additional hours, then neutralized by cautiously adding a 5% aqueoussodium bicarbonate solution and transferred to a separatory funnel. Theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated until formation of an abundant precipitate. The mixturewas cooled, the precipitate filtered and redissolved in hot ethylacetate, the insoluble material was filtered off and the filtrate cooledwhereby the recrystallized Zl-ace-toxy- 9a,19,19 trifluoro-A -pregnene115,170 diol-3,20-dione (Cpd. No. 86).

The Compounds Nos. 15 to 26, inclusive, upon treatment by the abovesequence of reaction afiorded the corresponding 9u-fl1l0l'0 derivatives.

Example XIV To a' solution of 4 g. of Compound No. in 40 cc. ofanhydrous chloroform, was added, over a period of 35 minutes 30 cc. of a0.45 N solution of dry hydrogen chloride in chloroform, under continuousstirring and maintaining the temperature around 0 C. The mixture wasthen stirred at 0C. for 1 hour further, diluted with water andthechloroform layer was separated, washed with aqueous sodiumbicarbonate solution and then with water, dried over anhydrous sodiumsulfate and evaporated under reduced pressure. Crystallization of theresidue from acetone-hexane gave 21-acetoxy-9a-chloro-19,19- dll l11'OI0-A -p1 6gI1eI1-1IB,17OL-dlOI-3,2O*dl0lfl (Cpd. No. 87).

By the same procedures there were obtained the 9wchloro derivatives ofcompounds Nos. 15 to 26, inclusive.

Example XV The compounds Nos. 86 and 87 were treated following theprocedure of Example III, thus giving respectively:

trione (Cpd. No. 88) and 21-acetoxy-9u-chloro-19,19- difluoro-A-pregnen-17u-ol-3,11,20-trione (Cpd. No. 89).

Example XVI The compounds Nos. 86, 87, 88 and 89 were treated inaccordance with Example IV, thus giving the corresponding free21-alcohols.

Example XVII A mixture of 1 g. of compound No. 73, 50 cc, of fresh- 'lydistilled acetophenone and 0.5 cc. of 72% perchloric acid was stirred atroom temperature for 1 hour. The resulting mixture was washed wit-hsodium bicarbonate solution and with water to neutrality, then it wassteam distilled and the product extracted with methylene chloride. Theextract was dried over anhydrous sodium sulfate and evaporated todryness. Crystallization from acetone-hexane yielded the16,17-acetophenonide of 19, 19-difluoro A pregnene 1 1p,16a,17a,2.1tetrol 3, 20-dione (Cpd. No. 90).

By the same procedure there were obtained the 16,17- acetophenonides ofcompound Nos. 74, 82, and 83.

Example XVIII The compound No. 69 was treated in accordance with theprocedure of Example XIII, thus atfording as final compound21-acetoxy-9a,19,19-trifluoro 16a,17a-isopropylidenedio'xy A pregnenellfl ol 3,20 dione (Cpd. No. 91).

Example XIX The compound No. 9-1 was treated successively according toExamples IV and VIII, thus furnishing respectively 9u,19,19 trifluoro1600,17rx isopropylidenedioxy- A -pregnene-11fi,21-diol-3,20-dione (Cpd.No. 92) and 9a,.19,19 trifluoro A pregnene l1,8,16oc,l7u,21-tetrol-3,20-dione (Cpd. No. 93).

We claim:

1. A compound of the following formula:

CH2OR 1:0 ---R r i wherein R and R are selected from the groupconsisting of hydrogen and a hydrocarbon residue of up to 8 carbonatoms; R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; and W isselected from the group consisting of hydrogen, fluorine and chlorine.

2. 19,19 difluoro A pregnene 11,8,17u,21 triol- 3,20-dione.

3. 19,19 difluoro 16a methyl A pregnene 11B, 17a,21-triol-3,'20-dione.

4. 19,19 difluoro 16B methyl A pregnene 11B, 170:,21-triol-3,20-dione.

5. 19,19 difluoro A pregnadiene 11,8,l7a,21- t-riol-3,20-dione.

6. 19,19 difluoro 160a methyl A pregnadienel1,8,l7a,2l-triol-3,20-dione.

7. 19,19 difluoro 16B methyl 11 pregnadiene- 1l,8,17 x,21-triol-3,20-dione.

8. 6a chloro 19,19 difluoro 16a methyl Apregnene-l1,6,17a,21-triol-3,20-dione.

9. 6a,l9,19 trifluoro 16a methyl A pregnene-11B,17u,21-triol-3,20-dione.

10. 19,19 difluoro A pregnene :,21 diol 3, 11,20-trione.

11. 19,19 difluoro 16oz methyl A pregnene-17a, 2 1-dio1-3,1 1,20-trione.

12. 19,19 difluoro 16,3 methyl A pregnene- 17a,21-diol-3,11,20-trione.

13. 19,19 difluoro A pregnadiene 1711,21 diol- 3,11,20-trione.

14. 19,19 difluoro 16a methyl A pregnadienel7a,21diOl-3,-11,20-1110118.

15. 19,19 difluoro 16,8 methyl A pregnadiene- 17a,2l-diOl-3,11,20-trione.

16. 6oz chloro 19,19 difluoro 16a methyl A pregnene-l7a,21-diol-3,11,20-trione.

17. 6a,19,19 trifluoro 16a methyl A pregnene-17u,21-diol-3,11,20-trione.

18. A compound of the following formula:

wherein Z is selected from the group consisting of a double bond and asaturated linkage between C-1 and C-2; X is a member of the groupconsisting of hydrogen, fluorine and chlorine; Y is selected from thegroup consisting of p-hydroxyl and ket-o; R is a'hydroxyl group; T is amember of the group consisting of hydrogen, ahydroxy, a-hydrocarboncarboxylic acyloxy group of less than 12 carbon atoms, a-methyl andB-methyl; R and T together represent the group /m )K ...0 s

wherein R and R are selected from the group consisting of hydrogen and ahydrocarbon residue of up to 8 carbon atoms; R is selected from thegroup consistingof hydrogen and a hydrocarbon carboxylic acyl group ofless than 12 carbon atoms; and W is selected from the group consistingof hydrogen, fluorine and chlorine.

19. 19,19 difluoro 16m methyl A pregnadiene-11,8,17a,21-triol-3,20-dione.

20. 19,19 difluoro 16a methyl A pregnadiene- 17a,2 1-diol-3,11,20-trione.

No references cited.

LEWIS GO'ITS, Primary Examiner.

1. A COMPOUND OF THE FOLLOWING FORMULA: